Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel

Abstract

Abstract-Vessel occlusion is the most frequent cause for impairment of local blood flow within the brain resulting in neuronal damage and is a leading cause of disability and death worldwide. Polyunsaturated fatty acids and especially ␣-linolenic acid improve brain resistance against cerebral ischemia. The purpose of the present study was to evaluate the effects of polyunsaturated fatty acids and particularly ␣-linolenic acid on the cerebral blood flow and on the tone of vessels that regulate brain perfusion. ␣-Linolenic acid injections increased cerebral blood flow and induced vasodilation of the basilar artery but not of the carotid artery. The saturated fatty acid palmitic acid did not produce vasodilation. This suggested that the target of the polyunsaturated fatty acids effect was the TREK-1 potassium channel. We demonstrate the presence of this channel in basilar but not in carotid arteries. We show that vasodilations induced by the polyunsaturated fatty acid in the basilar artery as well as the laser-Doppler flow increase are abolished in TREK-1 Ϫ/Ϫ mice. Altogether these data indicate that TREK-1 activation elicits a robust dilation that probably accounts for the increase of cerebral blood flow induced by polyunsaturated fatty acids such as ␣-linolenic acid or docosahexanoic acid. They suggest that the selective expression and activation of TREK-1 in brain collaterals could play a significant role in the protective mechanisms of polyunsaturated fatty acids against stroke by providing residual circulation during ischemia. (Circ Res. 2007;101:176-184.) Key Words: cerebral ischemia Ⅲ ␣-linolenic acid Ⅲ CBF Ⅲ vasodilatation Ⅲ two pore-domains channel TREK-1 A fter stroke, the function of cerebral arteries is critical to maintain cerebral perfusion and preserve neuronal integrity. The duration and intensity of the blood flow deficit are associated with the severity of brain damage. The level of cerebral blood flow (CBF) in brain tissue is coupled to an evident extent with vascular function and beyond neuronal consequences. It is well known that cerebral ischemia is associated with functional impairment of vascular tone within the occluded artery. 1 Polyunsaturated fatty acids (PUFAs) and particularly ␣-linolenic acid (ALA) and docosahexanoic acid (DHA) are potent protectors against focal and global ischemia. [2][3][4] The molecular mechanism of PUFA-induced neuroprotection has been recently clarified. 5 The main PUFA target seems to be the potassium channel, TREK-1, which belongs to the new family of two-pore domain potassium channels (K 2P ) and is known to be potently activated by PUFA. 6 -8 The importance of the TREK-1 channel in cerebral protection against ischemia has been validated by the fact that the protective effects of PUFA are drastically decreased in TREK-1-deficient mice. 5 The vascular wall represents the primary compartment of ischemic stroke. PUFA application confers neuronal protection, 2-4 but little is known about TREK-1 channel in cerebral vessels. A previous report shows the presence ...

Subchronic Alpha-Linolenic Acid Treatment Enhances Brain Plasticity and Exerts an Antidepressant Effect: A Versatile Potential Therapy for Stroke

“…In the domain of stroke disorders, there is growing evidence that the omega-3 precursor, ALA, is a potent protector in several models of global and focal ischemia (Xiao et al, 1998;Lauritzen et al, 2000;Blondeau et al, 2001Blondeau et al, , 2002Blondeau et al, , 2007Lang-Lazdunski et al, 2003;Heurteaux et al, 2004Heurteaux et al, , 2006a. In a mouse model of stroke, we found that a single injection of ALA, after the onset of stroke, significantly reduced infarct size and improved the neurological score 24-h post-ischemia.…”

“…Given our previous findings of vasoactive ALA-properties (Blondeau et al, 2007) and increases in neurogenesis being associated with vascular changes (Palmer et al, 2000), we cannot exclude a facilitation of neurogenesis and synaptogenesis related to a vasculature-mediated effect of subchronic ALA treatment.…”

“…In addition to the early and acute prevention of excitotoxicity induced by ALA treatment, we showed that ALA treatment increases cerebral blood flow and that this increase is related to an increased vasodilation leading to cerebral protection (Blondeau et al, 2007). The vasoactive ALA effect is also mediated by TREK-1 channels, because ALA-induced relaxation of cerebral arteries disappeared in TREK-1-deficient mice (Blondeau et al, 2007).…”

“…Our laboratory previously showed a neuronal protection induced by acute ALA treatment in different models of ischemia (Lauritzen et al, 2000;Blondeau et al, 2001Blondeau et al, , 2002Blondeau et al, , 2007Heurteaux et al, 2004Heurteaux et al, , 2006a. The beneficial ALA effects have been reported to be, in part, because of its activating effect on neuronal potassium TREK 1 channel, preventing the excessive release of excitotoxic glutamate while favoring a magnesium 2 + block at post-synaptic NMDA receptors.…”

Fatty acid methyl esters as a potential therapy against cerebral ischemia

“…It is interesting to note that the reduction of PAME released from PVAT can be observed in genetic hypertensive rats (Lee et al, 2011c). Furthermore, exogenous application of PA failed to induce aortic vasodilation (Blondeau et al, 2007;Lin et al, 2008) indicating that the methylation of PA is essential for vasodilation and PAME's bioactivity.…”